Rhenium-186-mercaptoacetyltriglycine-labeled Monoclonal Antibody for Radioimmunotherapy: In vitro Assessment, in vivo Kinetics and Dosimetry in Tumor-bearing Nude Mice (original) (raw)
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Health Physics, 2009
The monoclonal antibody (mAb) A33 detects a membrane antigen that is expressed on greater than 95% of metastatic human colorectal cancers. Previous studies have shown excellent tumortargeting of iodine-131 labeled murine and humanized forms of the mAb. A retrospective analysis of whole body clearance in the murine form was performed for comparison to the humanized form. Serial whole-body dose rate measurements were obtained for 55 treatments on 30 patients participating in phase I/II dose escalation studies of therapeutic iodine-131-murine A33 mAb. Whole-body retention fractions over time were derived. Each treatment was fit with exponential curves to determine the effective half-lives and corresponding clearance fractions. There was a large variability in the calculated mono-exponential clearance effective half-life time, with a mean value of 36.5 h +/− 8.5 h. A bi-exponential fit of all combined data shows that 60% of the administered dose rapidly clears with a biological half-time of 23.9 h and 40% clears with a slower biological half-time of 101.2 h. The whole body clearance proved to be more rapid in the murine form when compared with recent studies on the humanized form of radiolabeled A33 mAb. The variability in whole body clearance reinforces the need for patient-specific tracer dosimetry for clinical care and radiation safety precautions. In addition, the slower clearance of the humanized form of the A33 mAb requires longer term radiation safety precautions than the earlier murine form. As other monoclonal antibodies progress from murine to humanized forms, radiopharmacokinetics should be evaluated for clinical and radiation safety implications.
Annals of Nuclear Medicine, 2001
A murine IgGi against a Mr 45 kD tumor-associated glycoprotein in human colorectal cancer, A7, was radiolabeled with 186Re by a chelating method with a mercaptoacetyltriglycine (MAG3). Its specific activity was 1 19 MBq/mg, which would be high enough for a therapeutic purpose, and its immunoreactivity was preserved well as was 13q-A7 labeled by the chloramine-T method. Growth of human colon cancer xenografts, 9.14 + 0.44 mm in diameter, in nude mice was significantly suppressed by an intravenous dose of 4.48 MBq of 186Re-A7. The therapeutic outcome with 186Re-A7 was better than that with 4.63 MBq of 131I-A7. Toxicity of treatments assessed by body weight change was similar with both conjugates. These results are likely caused by the tumor size and more favorable physical properties of 186Re than those of 131I.
Biological considerations for radioimmunotherapy
Cancer research, 1990
We have examined three methods that may be useful for improving the therapeutic efficacy of antibody-targeted radionuclides. The principal limitation of radioimmunotherapy is myelotoxicity and thrombocytopenia. These are due mainly to the length of time the radioantibody remains in the blood. The clearance time of a radiolabeled immunoglobulin G (IgG) may be decreased by using fragments prepared from the IgG. Using murine monoclonal antibodies against human colonic cancer in an animal model with a transplantable human colonic tumor, we have shown that fractionated doses of 131I-labeled F(ab')2 fragments can provide similar tumoricidal activity as a single injection of IgG, but toxicity to the normal tissues is reduced significantly at this tumoricidal level. Thus, it is expected that improved tumoricidal activity may be achieved by further escalating the dose of F(ab')2 that is administered at each injection. An anti-antibody (second antibody) may also be used to remove an a...
International Journal of Cancer, 1998
Recent clinical results suggest that higher anti-tumor efficacy may be achieved with internalizing monoclonal antibodies (MAbs) at lower toxicity when labeled with Augerelectron, as compared to conventional -emitters. The aim of our study was to compare the toxicity and anti-tumor efficacy of the 125 I-labeled internalizing MAb, CO17-1A, with its 131 I-labeled form in a human colon cancer model in nude mice. Biodistribution studies were performed in nude mice bearing s.c. human colon cancer xenografts. For therapy, the mice were injected either with unlabeled 125 I-or 131 I-labeled CO17-1A at equitoxic doses. Control groups were left untreated, were given a radiolabeled isotype-matched irrelevant antibody or a tumor-specific, but noninternalizing antibody. The maximum tolerated activities (MTD) of 131 Iand 125 I-CO17-1A without artificial support were 300 µCi and 3 mCi, respectively. Myelotoxicity was dose-limiting; bone marrow transplantation allowed for an increase of the MTD to 400 µCi of 131 I-17-1A, whereas the MTD of 125 I-17-1A with bone marrow support had not been reached at 5 mCi. Whereas no significant therapeutic effects were seen with unlabeled CO17-1A, tumor growth was retarded with 131 I-CO17-1A. With the 125 I-label, however, therapeutic results were clearly superior. In contrast, no significant difference was observed in the therapeutic efficacy of the 131 I-vs. 125 I-labeled, noninternalizing antibodies. Our data indicate a superiority of Auger-electron emitters, such as 125 I, as compared to therapy with conventional -emitters with internalizing antibodies. The lower toxicity of Auger emitters may be due to the short path length of their low-energy electrons, which can reach the nuclear DNA only if the antibody is internalized (as is the case in antigen-expressing tumor tissue, but not in the stem cells of the red marrow). Int. J.
Pharmaceutical Biology, 1995
biological behavior (Mausner, 1993). Physical properties that are important to consider include the radionuclide half-life, the type, energy and branching ratio of particulate radiation and the gamma-ray energies and abundances. The physical half-life should be matched with the in vivo pharmacokinetics of the molecule under consideration. Time-dose fractionation is also an important criterion . For equal radioactivity concentrations in the target, radionuclides with long half lives will produce a lower absorbed dose rate than those with short half lives. The type of particulate emission also must be considered. Although Auger and low-energy conversion electrons can be potentially lethal , this effect can best be realized with intranuclear localization of the radionuclide, which does not generally occur with radiolabeled MAbs. Beta particles are less densely ionizing and have a range longer than a's or the Auger and conversion electrons so that the distribution requirements are less restrictive for RIT of bulky disease or for macrometastases. The gamma-ray energies and abundances are also important physical properties, because the presence of gamma rays allows the possibility of external imaging.
Nuclear Medicine and Biology, 1998
The increased interest in the availability of radionuclides for therapy has resulted from the recent success and potential importance of radiolabeled antibodies for both diagnosis and therapy. There is a widespread interest in the availability of 188Re for various therapeutic applications, particularly for attachment to tumor-specific monoclonal antibodies for radioimmunotherapy. This review provides a perspective of 188Re-direct labeled MAbs for radioimmunotherapy of solid tumors, normal organ biodistribution, absorbed radiation doses to normal organs and tumors, and the toxicity to bone marrow and normal tissues. Methods for calculation of mean absorbed radiation doses to the whole body, various normal organs, and tumors have been developed using source-organ residence times and the methods developed by the Medical Internal Radiation Dose (MIRD) committee. The toxicity for 188Re-labeled antibodies is predominantly hematopoietic, with platelets and white blood cells being most sensitive to the effects of radiation. Rhenium-188 would be the isotope of choice for radioimmunotherapeutic applications because of cost, availability, and favorable radiation characteristics. Rhenium-188 has a half-life of 16.9 h and maximum beta energy of 2.118 MeV. This isotope is particularly attractive because it can be supplied conveniently from 188W/188Re-radionuclide generator system.
Applied Radiation and Isotopes, 2001
188 Re is one of the radioisotopes expected to emerge as useful for therapy. Development of new radiopharmaceuticals based on 188 Re depends on the radiolabeling methods used, which would give stable complexes having prede®ned radiochemical properties and in vitro and in vivo stability. This paper has attempted to provide a perspective of 188 Re-labeled monoclonal antibodies, their radiolabeling characteristics, methods for quality control of radioimmunoconjugates and in vitro stability for radioimmunotherapy of solid tumors. The direct method of 188 Re radiolabeling of antibodies by reductive attachment of 188 Re in which free sulfhydryl groups have been generated by reduction of the intramolecular S±S disul®de bonds has been shown to be a promising approach in particular. Moreover, excellent methods have been developed to test the radionuclide, radiochemical purity and stability of 188 Re-radioimmunoconjugates using high performance liquid chromatography (HPLC) and paper chromatography. 7
Cancer Research, 1991
The use of l88Refrom an alumina-based "*W/1MRegenerator has been investigated for antibody radiolabeling. It was found that, with simple labeling techniques, '""Re can be used immediately after elution. The direct radiolabeling of intact antibodies with >S8Reis described. Lyophilized antibody preparations have been reconstituted with 18*Retaken directly from the generator at specific activities of up to 15 mCi of IS8Re per mg of antibody. Radiolabeling yields of 90 to 98% have been obtained, with the incorporation rate being dependent upon time and the relative concentrations of the reagents. It was determined that the conjugates were immunoreactive and stable when challenged by serum in vitro, with l8*Re-immunoglobulin G showing adequate resistance to reoxidation with no transfer of 18*Reto serum protein. l8*Re-antibody conjugates were shown to clear from the blood faster than the corresponding I3ll-labeled antibody, giving rise to good tumor/nontumor ratios at 24 to 72 h postinjection, while serum samples taken from the animals have shown that the circulating l8*Re remained bound to immunoglobulin G. The combination of the technologies of the 188\V/l8*Regenerator, the direct labeling methodology, and the use of single-vial lyophilized antibody makes the use of l88Re-radiolabeled monoclonal antibodies a simple and convenient method of cancer radioimmunotherapy with a /3-emitting radionuclide.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1989
A method of radioiodinating monoclonal antibodies such that the labeled antibodies do not undergo in vivo deiodination has been studied. The method utilizes conjugation of succinimidyl para-iodobenzoate to the antibody. The iodobenzoate was radiolabeled by using an organometallic intermediate to facilitate the reaction. Thus, succinimidyl para-tri-n-butylstannylbenzoate was radiolabeled in 60-90% radiochemical yield and subsequently conjugated to the antibody in 80-90% yield. Animal biodistribution studies were carried out with two separate anti-melanoma antibodies (9.2.27 and NR-M1-05) labeled by this method, and examined in nude mice bearing human melanoma tumor xenografts. Very large differences in the localization of radioactivity were observed in the thyroids and stomachs of mice when the iodobenzoyl-labeled antibodies were compared with the same antibodies labeled using the chloramine-T method of radioiodination. Few other significant differences in the tissue distribution of ...